Synthesis and anxiolytic effect of europium metallic complex containing lapachol [Eu(DBM)₃. LAP] in adult zebrafish through serotonergic neurotransmission: in vivo and in silico approach

Abstract

Anxiety-related mental health problems are estimated at 3.6% globally, benzodiazepines (BZDs) are the class of drugs indicated for the treatment of anxiety, including lorazepam and diazepam. However, concerns have been raised about the short- and long-term risks associated with BZDs. Therefore, despite anxiolytic and antidepressant drugs, there is a need to develop more effective pharmacotherapies with fewer side effects than existing drugs. The present work reported the synthesis, anxiolytic activity, mechanism of action in Adult Zebrafish (Danio rerio) and in silico study of a europium metallic complex with Lapachol, [Eu(DBM)₃. LAP]. Each animal (n = 6/group) was treated intraperitoneally (i.p.; 20 µL) with the synthesized complex (4, 20 and 40 mg/Kg) and with the vehicle (DMSO 3%; 20 µL), being submitted to the tests of locomotor activity and 96h acute toxicity. The light/dark test was also performed, and the serotonergic mechanism (5-HT) was evaluated through the antagonists of the 5-HTR₁, 5-HTR_2A/2C and 5-HTR_3A/3B receptors. The complex was characterized using spectrometric techniques, and the anxiolytic effect of complex may be involved the neuromodulation of receptors 5-HT3A/3B, since the pre-treatment with pizotifen and cyproheptadine did not block the anxiolytic effect of [Eu(DBM)₃. LAP], unlike fluoxetine had its anxiolytic effect reversed. In addition, molecular docking showed interaction between the [Eu(DBM)₃. LAP] and 5HT_3A receptor with binding energy −7.8 kcal/mol and the ADMET study showed that complex has low toxic risk. It is expected that the beginning of this study will allow the application of the new anxiolytic drugs, given the pharmacological potential of the lapachol complex.

Communicated by Ramaswamy H. Sarma

Keywords:

• Lapachol
• lanthanides
• zebrafish
• anxiety

Acknowledgments

The authors would like to thank the Brazilian Agencies: Fundação Cearense de Apoio ao Desenvolvimento Científico e Tecnológico (FUNCAP). Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Coordenação de Aperfeiçoamento de Ensino Superior (CAPES) for fellowships and financial supports.

Disclosure statement

The authors declare no conflict of interest.

Additional information

Funding

Hélcio Silva dos Santos acknowledges financial support from CNPq (Grant 306008/2022-0).